Tannin and anti-gliadin antibody compositions for treatment of a disease of the intestinal tract

ABSTRACT

The present invention relates to a composition for use in the treatment of an intestinal tract disorder caused by a gluten-associated protein, said composition comprising at least one agent which binds to the gluten-associated protein, characterized in that the composition is administered at the same time as or at most within 60 minutes after administration of at least one tannin to a patient.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/638,638, filed Jun. 30, 2017, which is a continuation of U.S.application Ser. No. 14/367,171, filed Jun. 19, 2014, now U.S. Pat. No.9,724,326, which is a national phase application under 35 U.S.C. § 371of International Application No. PCT/AT2012/050200 filed Dec. 19, 2012,which claims priority to Austrian Patent Application No. A 50010/2011,filed Dec. 19, 2011. The entire contents of each the above-referencedapplications are incorporated herein by reference.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The present invention relates to a composition for treating diseases ofthe intestinal tract which are caused by gluten and related substances.

2. Description of Related Art

Inflammatory processes in the intestinal tract may have various causesbut in most cases they are difficult to diagnose and even more difficultto treat. In recent years, diagnosis of so-called food intolerances hasbecome increasingly important in the professional medical world and thushas also yielded new findings for elucidating the causes of inflammatoryprocesses in the intestinal tract.

Many people also develop an intolerance to histamine and other biogenicamines. In this case the efficiency of the diamine oxidase enzyme is notsufficient to effectively degrade the biogenic amines ingested withfood. As a result, the excess histamine enters the bloodstream. Thoseaffected typically develop headaches, diarrhea, unpleasant flatulenceand other allergy-like symptoms after consuming certain foods.

The gluten intolerance, also known as celiac disease or sprue, is verycomplex. This disease is a complex combination of an absorption disorderand an interactive autoimmune reaction of the body, which to some extentalso requires a genetic HLA predisposition, namely the HLA-DQ2 or DQ8serotype. It is not yet understood why most of the population havingthis genetic predisposition develop a tolerance mechanism. Currently anumber of definitions of disease syndromes which are triggered by glutenand/or gliadin can be found in the literature. These include, amongothers:

Asymptomatic celiac disease (also known as silent celiac disease): nosymptoms either in the presence of gluten or in withdrawal; antibodiesare present, and there is an increased risk of developing severe celiacdisease.

Classical celiac disease: classical symptoms of malabsorption; diarrhea,steatorrhea, weight loss, failure to thrive. Usually diagnosed inchildren.

Subclinical celiac disease: tends to nonspecific symptoms such as irondeficiency, liver dysfunctions, some biopsy results may be available.

Symptomatic celiac disease: gastrointestinal/extraintestinal symptomswhen gluten is consumed; broad spectrum of symptoms.

Refractory celiac disease (RCD): malabsorption and villous atrophy aftermore than 12 months of a strict gluten-free diet. The serology isusually negative; positive serology also indicates dietary mistakes.

Type I RCD: normal phenotype of the interepithelial lymphocytes.

Type II RCD: unchecked clonal expansion of interepithelial lymphocytes,precursor to enteropathy-associated lymphoma.

Latent celiac disease: positive serology with unremarkable histology ofthe small intestine or normal histology of the mucosa of the smallintestine, which changes in response to administration of gluten orundiagnosed celiac disease or morphological deviations in the mucosa ofthe small intestine without any remarkable serology.

Potential celiac disease: positive serology, no villous atrophy.

Celiac disease autoimmunity: positive serology, characterized byelevated tTG (“tissue transglutaminase”) or EMA (“endomysial componentsof antibodies”) levels at a minimum of two measurement times.

Gluten intolerance: synonym for celiac disease or a nonspecificceliac-like disease that responds to a gluten-free diet.

Non-celiac gluten sensitivity (NCGS): general term for immunological,morphological or other symptoms that (may) occur in conjunction withingestion of gluten. The innate immunity is activated but the serologyis negative and there is no villous atrophy. This is a local glutenallergy with only local secretion of IgE.

Gluten-associated disorders: gluten ataxia, Duhring's disease(dermatitis herpetiformis).

A gluten allergy (“wheat allergy”) is a completely differentbiochemically and physiologically. This is a classical IgE-mediatedallergy to gluten, where sensitization of the lungs usually occursthrough wheat flour dust.

The non-allergic immune response in celiac disease is triggered mainlyby the alcohol-soluble protein fractions (so-called prolamines) of wheat(gliadin), rye (secalin), barley (hordein) and oats (avenin) as well asother fragments after peptic-tryptic digestion in the stomach.

These proteins as a group are referred to below as “gluten-relatedproteins.” These proteins induce the immunological reaction spectrum ofceliac disease in a manner that is reproducible in vitro and in vivo.They contain characteristic “amino acid repeats” consisting of proteinsand glutamines. Examples that can be mentioned include the typicalpeptides: α-gliadin: LQLQPF(PQPLPY)₃PQPQPF; γ-gliadin:FLQPQQPF(PQQ)₂PY(PQQ)₂PFPQ; LMW-glutenin: QQQQPPFSQQQQSPFSQQQQ;HMW-glutenin:(GYYPTSPQQ)_(n). The main trigger for the entirephysiological celiac disease process is the passage of gluten that isonly partially digested in the stomach through the epithelial cell layerof the small intestine into the lamina behind it.

SUMMARY OF THE INVENTION

The object of the present invention is to make available agents forpreventing, reducing or ameliorating the inflammatory or immunologicalprocesses triggered by one or more gluten-related proteins in theintestinal tract.

The present invention therefore relates to a composition for use intreating a disease of the intestinal tract, which is triggered by agluten-related protein, comprising at least one agent that binds togluten-related protein, characterized in that the composition isadministered to a patient simultaneously with or at most within 60minutes (preferably 50 minutes, more preferably 40 minutes, even morepreferably 30 minutes) after administration of at least one tannin.

According to the invention, this object is achieved by the combinationof two means which are supplied orally in chronological sequence. Thepresent invention presents for the first time a functional combinationof two fundamentally different mechanisms of action. Firstly, theintestinal mucosa is stabilized with the help of tannins and absorptionof potentially toxic substances is greatly reduced. At the same time orimmediately thereafter, the toxic substances and/or mediators are boundby means of specific adductors and are thus removed from thephysiological absorption process.

One object, namely the binding or masking of gluten-related proteins, isachieved according to the invention by means of specific antibodies,antibody fragments (e.g., light chains, antigen-specific binding sitesand the like), aptamers, DARPINS or other suitable specific bindingprotein structures with which those skilled in the art are familiar. Theproduction of these masking substances can be adapted to the respectiveprior art and optimized.

Antibodies or their fragments, which are secreted in egg yolk by layinghens following immunization with a desired antigen, are preferred. Theseimmunoglobulins (IgY) have a structure resembling that of mammalianimmunoglobulins IgG and IgE, but they do not interact with the mammalianimmune system because of the absence of the FC domains.

Since the antibodies must be introduced into the intestine in a naturalbioactive form, IgY from egg yolks is recommended preferentially becausein this case an interaction with FC receptors of immune cells,rheumatoid factor and the complement system can be ruled out. Thisformation of specific IgY to gluten has already been performed (see US2011/0008362, for example). As an alternative to IgYs, other polyclonalor monoclonal antibodies or their fragments may of course also be usedif they can be modified according to the state of the art and madetolerable for humans. Additional antibodies in the sense of theinvention can also be obtained from lizards or the blood of lungfish.Also preferred in the sense of the invention is the use of aptamers,which recognize specifically those epitopes that trigger or controladverse reactions in the gastrointestinal region. Those skilled in theart are familiar with the development and characterization of theseaptamers.

The term “gluten-related proteins” as used here includes gliadin,secalin, hordein and avenin as well as their fragments afterpeptic-tryptic digestion in the stomach, but gliadin and its fragmentsare especially preferred. The following terms may therefore be used assynonyms for “gluten-related proteins”: “gliadin, secalin, hordein andavenin and their fragments after peptic-tryptic digestion in thestomach,” “gliadin, secalin, hordein and avenin and fragments producedtherefrom by pepsin and/or trypsin” or “gliadin, secalin, hordein,avenin and fragments thereof.” Fragments in the sense of the presentinvention consist of 5 to 100 amino acids, preferably 10 to 50 aminoacids.

Tannins fulfill the task of stabilizing the intestinal mucosa. Tanninsare a large family of related polyphenolic substances that occur inhigher plants and algae. They are branched macromolecules according tothe building block principle which share certain physicochemicalproperties: water solubility and the ability to attach themselves toproteins and to crosslink them, forming precipitates with alkaloids, andbinding of chelate complexes with Fe^(III) salts. According to theinvention, various tannins, even in mixed form, may be used forstabilizing the mucous membranes. Tannins of the catechol tannin,Lamiaceae tannin or algal tannin type are preferred for use here.Sources of tannins include, for example: oak apples (Gallae); witchhazel leaves (Hamamelidis folium); walnut leaves (Juglandis folium); oakbark (Quercus cortex); ratanhia root (Raatanhiae radix); blood root(Tormentillae rhizome); blueberries (Myrtilli fructus); catechu; Rubusfruticosus; Potentilla anserina; Fragaria vesca; Agrimonia eupatoria;Alchemilla xanthochlora; Plantago major; Plantago lanceolata, Rosagallica; Sanguisorba officinalis or also the seeds of dates, grapes,etc. Synthetic tannins may optionally also be used according to theinvention, for example, polymers of acrylates, polyurethanes,isocyanates, derivatives of aldehydes but also the salts of minerals,for example, alums, chromium salts or zirconium salts may also be used.

According to one particularly preferred embodiment, the at least onetannin is selected from the group consisting of tannins, catecholtannins, Lamiaceae tannins and algal tannins.

The ability to crosslink proteins is based on a nonspecific addition ofthe phenolic structures to hydrophobic pockets as well as thedevelopment of hydrogen bridges between the hydroxyl groups of tanninand the side chains of amino acids. Addition of the tannins leads tofolding and, in a sufficient concentration, crosslinking of theproteins.

Tannins are especially preferably used after being precipitated inadvance with protein in a 20:80 ratio [tannin:protein], preferably35:65, especially preferably 50:50 (for example, by bringing the tanninin contact with the protein/polypeptide). Proteins having a molecularweight between 50 kDa and 500 kDa in general may be used as the protein.

It has surprisingly been found that a double effect can be achieved byprecipitating the tannin in advance with an antibody or binding protein:the resulting macromolecule combines the ability to crosslink theintestinal mucosa with the simultaneous ability to bind toxic antigensand substances and to reduce their bioavailability. The use of bindingprotein structures, which are precipitated with a tannin in advance in aratio of 20:80 [tannin:protein], preferably 35:65, in particularpreferably 50:50, is particularly preferred.

The present invention therefore relates to a composition comprising thecombination of at least one tannin and at least one substance forbinding or masking gluten-related proteins, so that the combination canbe administered orally, with the goal of treating inflammatory ornonallergic immunological processes that are triggered by one or moregluten-related proteins in the intestinal tract.

In addition to the substance for binding or masking the gluten-relatedproteins and the tannin, bioactive microorganisms may also beadministered to support the degradation of these toxic substances and/ormediators and thus suppress other potential pathological processes.

In another variant of the composition according to the invention, thespecific bound toxic substances, peptides and/or antigens or mediatorswhich also travel through the intestinal tract with the digested foodmixture may also be degraded subsequently due to the administration ofspecial bacterial proteases. In the case of celiac disease, the enzymeof choice is prolylendopeptidase (PEP; EC 3.4.21.26), which occurs inall living creatures. It is capable of degrading peptides that areformed from gluten and gliadin as the single enzyme to a certain extent.PEP occurs primarily as an intracellular enzyme; a few microorganisms,e.g., Flavobacterium meningosepticum, A. niger, as well as variousLactobacilli are also capable of secreting this enzyme. Additionalmicroorganisms according to the invention include bacteria from thehuman oral cavity, for example, fusobacteria or actinomycetes.

The binding protein structures and tannins are preferably administeredin a defined interval of time: firstly, the tannin preparation isadministered orally in a period of time from 0 to 60 minutes, preferably10 to 40 minutes, especially preferably 15 to 30 minutes before eatingfood that contains gluten.

According to one preferred embodiment of the present invention, theantibody, antibody fragment, aptamer and/or DARpin is directed againstgliadin and/or fragments thereof, in particular against gliadin cleavedby tryptic and/or peptic action or physiologically equivalentmetabolites of gluten or gluten fractions.

The at least one protein or polypeptide, in particular at least oneantibody is preferably of a recombinant origin.

According to yet another preferred embodiment of the present invention,the at least one antibody is a polyclonal antibody from mammals,polyclonal antibody of avian origin, an antibody from lizards, amonoclonal antibody or an antibody from the blood of lungfish.

According to one preferred embodiment of the present invention, thecomposition according to the invention comprises eukaryotic and/orprokaryotic cells which are capable of reducing and/or suppressinginflammatory processes in the stomach and/or intestinal tract.

The cells present in the composition according to the invention arepreferably capable of secreting proteins (such as enzymes, for example)that are capable of reducing and/or suppressing inflammatory processesin the intestinal tract, which are responsible for the development of aninflammatory disease.

According to one particularly preferred embodiment, the compositioncomprising at least one tannin is administered for treatment of aninflammatory disease of the intestinal tract in combination with atleast one second agent for treatment of an inflammatory disease of theintestinal tract, wherein the at least one second agent induces ormediates at least one protein or polypeptide which binds at least onesubstance (actively) which induces or mediates the inflammatory diseaseand comprises eukaryotic cells and/or prokaryotic cells which arecapable of reducing and/or suppressing inflammatory processes in thestomach and/or intestinal tract. In other words, the compositionaccording to the invention, comprising at least one tannin, isadministered in combination with a composition comprising at least oneprotein or polypeptide and a composition comprising eukaryotic cellsand/or prokaryotic cells, both of which are defined above. The twocompositions mentioned last may be supplied in either one or at leasttwo individual dosages forms for administration.

According to one preferred embodiment of the present invention, theeukaryotic and/or prokaryotic cells are selected from the groupconsisting of Flavobacterium sp., Lactobacillus sp., Aspergillus sp. andBifidobacterium sp.

The at least one tannin is preferably precipitated in advance with atleast one protein.

According to another preferred embodiment of the present invention, theat least one agent, which binds to the gluten-related protein, and theat least one tannin are present in a formulation for controlled releasein the stomach and/or intestinal tract, preferably the intestinal tract.

Those skilled in the art are familiar with agents for formulating activeingredients, which make it possible to provide a composition having theproperty of releasing, under certain conditions, the active ingredientsincorporated into the composition. Such agents are used pharmaceuticallyto release active ingredients exclusively in the intestinal tract, forexample. This has the advantage that the active ingredients can bepassed through the stomach into the intestine by having an entericcoating that is resistant to gastric fluid.

The term “formulation for controlled release” comprises not only entericdosage forms and/or formulations but also “delayed release” for releasein the intestine with a time lag, sugar-degradable polymer coatings forrelease in the large intestine, coatings as a gel barrier for targetedrelease in the intestine depending on the thickness of the barrier,water-insoluble coatings with pore-forming agents which delay therelease depending on the pore size and quantity, pH-sensitive coatingsfor release according to the physiological pH gradient, bioadherentcoatings (chitosan, polyacrylates) that interact with the mucus andretain the dosage form, floating dosage forms for release in the stomachdue to the fact that swelling occurs in the stomach and passage throughthe pylorus is prevented, processing in pellet form in a size of lessthan 1 to 3 mm for rapid passage of the active ingredients through thepylorus and transferred to the intestine.

It has proven particularly advantageous according to the invention thatthe tannins are administered before the composition according to theinvention comprising the at least one agent that binds thegluten-related protein is administered before the composition accordingto the invention comprising the at least one agent because then themucus membranes, in particular the intestinal mucus membranes are wettedwith the tannins used according to the invention before the arrival ofthe aforementioned agents. This makes it possible first to stabilize themucosa whereupon the actual active ingredients can be administered fortreatment of the inflammatory disease.

The composition comprising at least one tannin is therefore administeredat least one minute, preferably at least five minutes, more preferablyat least ten minutes, most preferably at least 20 minutes before the atleast one agent for treatment of an inflammatory disease of theintestinal tract.

According to one preferred embodiment of the present invention, the atleast one tannin is administered in an amount of 10 mg to 10,000 mg,preferably 20 mg to 5000 mg, more preferably 50 mg to 2500 mg,especially preferably 100 mg to 2000 mg.

According to another preferred embodiment of the present invention, theat least one protein or polypeptide which binds to at least onesubstance (e.g., antigen) that induces or mediates the glutenintolerance is administered in an amount of 1 mg to 100,000 mg,preferably 5 mg to 50,000 mg, more preferably 10 mg to 20,000 mg,especially preferably 15 mg to 15,000 mg.

According to one particularly preferred embodiment of the presentinvention, the eukaryotic cells and/or prokaryotic cells areadministered in an amount of 10⁹ to 10¹⁴, preferably 10¹⁰ to 10¹³.

The binding protein structures and tannins, which are used according tothe invention, are administered according to the invention in a definedinterval of time: first, the tannin preparation is administered orallywithin a period of 0-60 minutes, preferably 10-40 minutes, in particularpreferably 15-30 minutes before eating the food that contains gluten.

When the compositions according to the invention are administeredorally, they are formulated accordingly (for example, with an entericcoating that is resistant to gastric acid).

Yet another aspect of the present invention relates to a set for use intreatment of a disease of the intestinal tract, which is caused by agluten-related protein, comprising at least one container that holds atleast one tannin and at least one additional container that holds thecomposition according to the invention.

According to one preferred embodiment of the present invention, the setcomprises compositions as defined above and is used for the purposesindicated above and in the manner described above.

ADDITIONAL EMBODIMENTS

-   1. A composition comprising at least one tannin for treatment of an    inflammatory disease of the stomach and/or the intestinal tract,    wherein the composition is administered in combination with at least    one second agent for treatment of an inflammatory disease of the    stomach and/or the intestinal tract.-   2. The composition according to embodiment 1, characterized in that    the inflammatory disease of the stomach and/or of the intestinal    tract is selected from the group consisting of celiac disease,    Crohn's disease, colitis, in particular cystic colitis, hemorrhagic    colitis, ischemic colitis, pseudomembranous colitis or ulcerative    colitis, irritable bowel and gastritis.-   3. The composition according to embodiment 1 or 2, characterized in    that the at least one second agent for treatment of an inflammatory    disease of the stomach and/or of the intestinal tract comprises at    least protein or polypeptide, which binds at least one substance    that induces or mediates the inflammatory disease.-   4. The compositions according to embodiment 3, characterized in that    the at least one protein or polypeptide is an antibody, an aptamer    and/or a DARpin (“designed ankyrin repeat protein”) directed against    a substance which induces or mediates the inflammatory reaction, or    a specific receptor directed against an active ingredient that    induces or mediates the inflammatory reaction.-   5. The composition according to embodiment 4, characterized in that    the at least one antibody, aptamer and/or DARpin is directed against    gliadin and/or fragments thereof, in particular against tryptically    and/or peptically cleaved gliadin or physiologically equivalent    metabolites of gluten or gluten fractions.-   6. The composition according to any one of embodiments 3 or 5,    characterized in that the at least one protein or polypeptide, in    particular the at least one antibody is of a recombinant origin.-   7. The composition according to embodiment 4 or 5, characterized in    that the at least one antibody is a polyclonal antibody from    mammals, a polyclonal antibody of avian origin, an antibody from    lizards, a monoclonal antibody or an antibody from the blood of    lungfish.-   8. The composition according to any one of embodiments 1 to 5,    characterized in that the at least one agent for treatment of an    inflammatory disease of the stomach and/or the intestinal tract    comprises eukaryotic cells and/or prokaryotic cells, which are    capable of reducing and/or suppressing inflammatory processes in the    stomach and/or the intestinal tract.-   9. The composition according to embodiment 8, characterized in that    the eukaryotic and/or prokaryotic cells are selected from the group    consisting of Flavobacterium sp., Lactobacillus sp., Aspergillus sp.    and Bifidobacterium sp.-   10. The composition according to any one of embodiments 1 to 9,    characterized in that the at least one tannin is selected from the    group consisting of tannins, catechol tannins, Lamiaceae tannins and    algal tannins.-   11. The composition according to any one of embodiments 1 to 8,    characterized in that the at least one tannin is precipitated in    advance with at least one protein.-   12. The composition according to embodiment 11, characterized in    that the at least one protein is an antibody defined as in one of    embodiments 4 to 7.-   13. The composition according to any one of embodiments 1 to 10,    characterized in that the at least one tannin and the at least one    agent for treatment of an inflammatory disease of the stomach and/or    of the intestinal tract are present in a formulation for controlled    release in the stomach and/or the intestinal tract, preferably the    intestinal tract.-   14. The composition according to any one of embodiments 1 to 13,    characterized in that the composition comprising at least one tannin    is administered simultaneously with and/or before the at least one    agent for treatment of an inflammatory disease of the stomach and/or    of the intestinal tract.-   15. The composition according to any one of embodiments 1 to 14,    characterized in that the composition comprising at least one tannin    is administered at least one minute, preferably at least five    minutes, more preferably at least ten minutes, most preferably at    least 20 minutes before the at least one agent for treatment of an    inflammatory disease of the stomach and/or of the intestinal tract.-   16. The composition according to any one of embodiments 1 to 15,    characterized in that the composition, comprising at least one    tannin, is administered in an amount of 100 mg to 10,000 mg,    preferably 100 mg to 5,000 mg, more preferably 100 mg to 2,500 mg,    especially preferably 500 mg to 2,000 mg.-   17. The composition according to any one of embodiments 3 to 7 and    10 to 16, characterized in that the at least one protein or    polypeptide, which binds to the at least one substance that induces    or mediates the inflammatory disease, is administered in an amount    of 200 mg to 100,000 mg, preferably 200 mg to 50,000 mg, more    preferably 200 mg to 20,000 mg, in particular preferably 500 mg to    15,000 mg.-   18. The composition according to any one of embodiments 8 to 17,    characterized in that the eukaryotic and/or prokaryotic cells are    administered in an amount of 10⁹ to 10¹⁴, preferably 10¹⁰ to 10¹³,-   19. A set for treatment of an inflammatory disease of the stomach    and/or of the intestinal tract, comprising at least one container    with at least one tannin and at least one additional container with    at least one agent for treatment of an inflammatory disease of the    stomach and/or of the intestinal tract.-   20. The set according to embodiment 19, as defined in one of the    embodiments 1 to 18.

1.-27. (canceled)
 28. A combination preparation suitable for a treatmentof a disease of an intestinal tract of a subject, the combinationpreparation comprising: a first dosage form, wherein the first dosageform comprises at least one agent that binds to a gluten-relatedprotein; and a second dosage form, wherein the second dosage formcomprises at least one tannin.
 29. The combination preparation of claim28, wherein the first and the second dosage forms are further defined asoral dosage forms.
 30. The combination preparation of claim 28, whereinthe agent comprises a protein or polypeptide.
 31. The combinationpreparation of claim 28, wherein the agent is an antibody, an antibodyfragment, an aptamer, a designed ankyrin repeat protein, or a specificreceptor directed against the gluten-related protein.
 32. Thecombination preparation of claim 31, wherein the agent is animmunoglobulin Y antibody.
 33. The combination preparation of claim 31,wherein the agent is a polyclonal antibody from a mammal, a polyclonalantibody from a bird, an antibody from a lizard, a monoclonal antibody,or an antibody from lungfish blood.
 34. The combination preparation ofclaim 31, wherein the agent is an anti-gliadin antibody or agliadin-binding fragment thereof.
 35. The combination preparation ofclaim 28, wherein the disease of the intestinal tract is caused by agluten-related protein.
 36. The combination preparation of claim 28,wherein the disease of the intestinal tract is a celiac disease.
 37. Thecombination preparation of claim 36, wherein the celiac disease isasymptomatic celiac disease, classical celiac disease, subclinicalceliac disease, symptomatic celiac disease, refractory celiac disease,latent celiac disease, potential celiac disease, celiac diseaseautoimmunity, gluten intolerance, non-celiac gluten sensitivity, or agluten-associated disorder.
 38. The combination preparation of claim 28,wherein the at least one tannin is a gallotannin, catechol tannin,Lamiacea tannin, or algal tannin.
 39. The combination preparation ofclaim 28, further comprising at least one bacterial protease.
 40. Thecombination preparation of claim 28, further comprisingprolylendopeptidase.
 41. The combination preparation of claim 28,further comprising at least one eukaryotic and/or prokaryotic cellcapable of reducing and/or suppressing inflammatory processes in astomach and/or an intestinal tract.
 42. The combination preparation ofclaim 41, wherein the at least one cell is further defined as a cell ofFlavobacterium sp., Lactobacillus sp., Aspergillus sp., orBifidobacterium sp.
 43. The combination preparation of claim 41, whereinthe composition comprises an amount of the at least one cell of 10⁹ to10¹⁴ cells.
 44. The combination preparation of claim 28, wherein thecombination preparation comprises 10 mg to 10,000 mg of the at least onetannin.
 45. The combination preparation of claim 28, wherein thecombination preparation comprises 1 mg to 15,000 mg of the at least oneagent that binds to a gluten-related protein.
 46. A kit suitable for atreatment of a disease of an intestinal tract, the kit comprising atleast one dose of at least one tannin and at least one dose of at leastone agent that binds to a gluten-related protein.
 47. The kit of claim46, wherein said doses are further defined as oral doses.